Fibrosis, a disorder belonging to a group of fibroproliferative conditions, is seen in different organs such skin, liver, lung, kidney and arteries. It is estimated that approximately 40% of all deaths in the United States are caused, in part, by fibroproliferative disorders. Excessive accumulation of extracellular matrix due to either over production of matrix such as fibronectin, type I and III collagens, low levels of matrix degrading enzymes such as matrix metalloproteinases (MMPs) or both are the common features of all of these fibrotic conditions.
As in all other organs, wound healing in the skin is a dynamic process involving tissue response to different types of insults. This process involves a continuous sequence of signals and responses in which platelets, fibroblasts, epithelial, endothelial and immune cells come together outside of their usual domain in order to orchestrate the very complex process of tissue repair. These signals, which are mainly growth factors (GFs) and cytokines, orchestrate the initiation, continuation and termination of wound healing (Scott et al. 1994). An imbalance in the synthesis and release of cytokines and GFs at the wound site may result in either retarded wound healing (e.g. in diabetic and elderly populations) or over-healing (e.g. fibroproliferative disorders, complication following surgical incision, traumatic wounds, and severe thermal injury). Thus, an important component of wound healing is its timely cessation and without such a timely cessation there may be a buildup of excess matrix, a deleterious fibrotic condition seen in millions of patients worldwide.
Matrix metalloproteinases (MMPs) represent a group of diverse proteolytic enzymes involved in ECM turnover and connective tissue remodeling during physiological conditions such as embryonic growth and development, uterine involution, bone growth, bone resorption and wound healing. The level of MMP expression in normal cells is low and that allows healthy connective tissue remodeling. However, an imbalance in expression of MMPs has been implicated in a number of pathological conditions such as dermal fibrosis, rheumatoid arthritis, atherosclerosis, and tumor invasion and metastasis.
Current treatment modalities for any fibrotic condition including dermal fibro-proliferating disorders such as hypertrophic scarring (HSc) and keloid remain unsatisfactory. Accordingly, it would be desirable to have therapeutic strategies for the treatment of various fibrotic diseases and conditions.